DESCRIPTION: The hallmark of sun exposure is the tanning response, the outcome of increased melanin synthesis by epidermal melanocytes and enhanced transfer of melanosomes from melanocytes to keratinocytes. Constitutive pigmentation determines the extent of the melanogenic response to sun exposure, and the poor tanning response of individuals with skin type I or II is associated with increased risk for skin cancer. Ultraviolet light has direct genotoxic effects, as well as indirect cellular effects which are mediated by increased synthesis of various paracrine/autocrine epidermal factors. Factors known to regulate pigmentation are alpha-melanotropin (alpha-MSH) and adrenocorticotropic hormone (ACTH) which are mitogenic and melanogenic for human melanocytes, and endothelin-1 which is a mitogen for, and a modulator of melanogenesis in, these cells. Recently, it was reported that variants of the melanocortin-1 receptor gene are expressed by skin type I and II individuals, suggesting a role for this receptor in determining the pigmentary response to sun exposure. alpha-Melanotropin mediates its effects primarily by activating the cAMP-dependent pathway. We found that activation of the cAMP pathway in human melanocytes is pivotal for the melanogenic response to ultraviolet light. Endothelin-1 activates multiple signaling pathways, including cAMP, intracellular Ca+2, protein kinase C, and tyrosine kinase-dependent pathways. Also, endothelin-1 seems to be important for the melanogenic response of human melanocytes to ultraviolet light. Endothelin-1 stimulates human melanocyte proliferation in a dose-dependent manner, but has a biphasic effect on the activity and protein level of tyrosinase: a stimulatory effect at subnanomolar concentrations, and an inhibitory effect at higher concentrations. This modulation of tyrosinase correlates with the extent of mobilization of intracellular Ca+2 by different concentrations of endothelin-1, a mechanism that might be significant in the physiologic regulation of melanogenesis. Endothelin-1 and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation and addictively to modulate melanogenesis. We hypothesize that the response of normal human melanocytes to ultraviolet light is regulated by the crosstalk of different signaling pathways that are activated by endothelin-1 and alpha-melanotropin. Based on this, we propose to elucidate the significance of the melanocortin-1 receptor, the role of endothelin-1, and the participation of the cAMP and Ca+2-dependent pathways in the regulation of human melanocyte proliferation and melanogenesis. particularly in response to ultraviolet light.